Pain-killing preparation

ABSTRACT

A pain-killing preparation comprises poly-N-vinylpyrrolidone with a molecular mass of from 30,000 to 40,000, morphine hydrochloride and water at the following concentrations of the components, g per liter of water: 
     
         ______________________________________                                    
 
    
     poly-N--vinylpyrrolidone                                                  
                   250 to 310                                             
morphine hydrochloride                                                    
                     5 to 6.25.                                           
______________________________________

FIELD OF THE INVENTION

The present invention relates to the art of medicine and, morespecifically, to a pain-killing preparation featuring a long-lastinganalgetic effect.

STATE OF THE ART

Pain-killers (analgetics) widely employed at the present time such aspromedol, pontapone, and morphine provide but a short-time analgeticeffect. After serious operations such as oncological ones a multipleadministration of such preparations is necessary (4-5 times a day) whichis associated with the risk of adaptation. A short-time effect of theseanalgetics provides a number of disadvantages during a long-timetransportation of patients with pronounced pain syndroms, as well ascomplicated operation of the medical personnel in the case ofpain-killing in incurable patients both at home and in stationaries.With all this in consideration, preparations with a long-time analgeticeffect are of a great importance for medicine.

The duration of the analgetic effect during pain-killing procedures canbe extended by introduction, into an aqueous solution of the analgetic,of a high-molecular compound such as poly-N-vinylpyrrolidone (PVP). Aknown pain-killer consists of poly-N-vinylpyrrolidone, morphinehydrochloride and water (Experimental Surgery and Anestesiology, No. 6,1971, p. 70, "Meditsina" Publishing House /in Russian/). In thispain-killer use is made of said high-molecular compound with a molecularmass of from 40,000 to 80,000).

Administration of this pain-killing preparation provides a constantconcentration of morphine hydrochloride in blood plasma for a long timeperiod thus ensuring a long duration of the pain-killing effect (morethan 24 hours in 34.5% of patients). As a result, it has become possibleto effect a single intramuscular injection of the preparation instead of4-6 usual injections of common analgetic. In contrast to pure morphinehydrochloride, the pain-killer does not cause inhibition of breathingand does not cause nausea and vomiting nausea, exerts a retarding effecton the intestinal perilstatics and does not affect the cardio-vascularsystem due to the fact that concentration of morphine hydrochloride inblood is insignificant.

However, this pain-killing preparation possesses a number ofdisadvantages. A high concentration of poly-N-vinylpyrrolidone with amolecular mass of from 40,000 to 80,000 (60%) in water is responsiblefor a high viscosity of the solution. This hinders its intramuscularinjection and necessitates the use of special needles for administrationof the preparation by means of a syrynge; a lasting infiltration oftissues at the site of administration of the pain-killer takes place.

Furthermore, in a polymer with the above-mentioned molecular mass up to6% by weight of fractions are present which have a molecular mass offrom 250,000 to 750,000. This is highly undesirable, since thesehigh-molecular fractions are detailed in the organism.

DISCLOSURE OF THE INVENTION

The present invention is directed to a pain-killing preparation whichpossesses a more lasting pain-killing effect, contains no high-molecularfractions detailed in the organism and which, upon its administration,would not cause lasting infiltration of tissues.

This object is accomplished by a pain-killing composition consisting ofpoly-N-vinylpyrrolidone, morphine hydrochloride and water, wherein,according to the present invention poly-N-vinylpyrrolidone is used witha molecular mass of from 30,000 to 40,000 at the followingconcentrations of the components, g, per liter of water:

    ______________________________________                                        poly-N--vinylpyrrolidone                                                                             250 to 310                                             morphine hydrochloride  5 to 6.25                                             ______________________________________                                    

The pain-killing preparation according to the present inventioncomprises a low-viscosity transparent liquid of a yellowish color.

In comparison with the analgetics currently available in the medicinalpractice, the pain-killer according to the present invention possesses ahigh analgetic activity, provides no irritating effect on tissues andits toxicity is not different from that of morphine hydrochloride.

The pharmacological effect of the pain-killing preparation according tothe present invention has been studied on rats and mice. The experimentshave been carried out in comparison with the standard solution ofmorphine hydrochloride.

In all the experiments the doses have been calculated in respect of thestandard morphine hydrochloride upon a single-time administration. Theresults of the experiments have been statistically processed at p=0.05.The test and control groups amounted to 20 animals.

The analgetic activity has been determined on white mice weighing 16-18g upon causing a mechanical painful irritation by the Haffner method(1929) and on rats weighing 90-120 g. In the case of rats the thresholdof the pain sensitivity (determined by squeak) was recorded by applyingelectrical pain irritation by means of electrodes implanted under thetail skin. The test results are shown in the following Table 1

                  TABLE 1                                                         ______________________________________                                        Analgetic activity                                                                    Dose of pain-killer,                                                                      Analgetic effect, hours                                             calculated for          Standard                                              morphine      Pain-killer                                                                             solution                                              hydrochloride,                                                                              of the    of morphine                                 Test animals                                                                            mg/kg         invention hydrochloride                               ______________________________________                                        mice                                                                          (hypodermal                                                                   administration)                                                                         20            20.5      3.5                                         rats                                                                          (intramuscular                                                                administration)                                                                         10            12.5      3.0                                         ______________________________________                                    

The pain-killing preparation according to the present invention providesthe analgetic effect characteristic for morphine hydrochloride; however,as regards the intensity and duration of pain-killing effect it isconsiderably superior thereover, as it is seen from the data shown inthe above Table.

The local irritation effect of the pain-killing composition according tothe present invention has been studied upon the intramuscularadministration thereof to rats. The animals were slaughtered (bydecapitation) after 4, 18, 24, 48 and 72 hours after the administrationof the pain-killer in the amount of 0.5 ml which corresponded to thedose of 2.5 mg/kg as calculated for the standard morphine hydrochloride.The skin and muscles at the site of administration of the pain-killingpreparation have been subjected to histological studies. Four hoursafter the administration of the pain-killing preparation according tothe present invention punctate hemorrhages were observed at the site ofpuncture of the muscles and a considerable amount of the pain-killer inthe intermuscular voids; 18 hours after the administration at the siteof the injection there were also detected punctate hemorrhages andtraces of the administered pain-killer. No inflammatory changes in thesurrounding tissues were observed. 24 hours after administration in thesubcutaneous fat, only pale punctate hemorrhages at the site of skinpuncture were observed; no changes in the surrounding tissues weredetected. During the following 48 and 72 hours a punctate crust isdetected at the site of skin puncture and pale, barely noticeablepunctate hemorrhages in the area of 1-2 mm radius from the injectionspot. Therefore, no pathological changes in muscles and subcutaneous fatare observed.

Acute toxicity of the pain-killing preparation according to the presentinvention has been determined in experiments on mice upon a hypodermaladministration of the doses: 100, 200, 300, 400, 500 and 600 mg/kg.Variations of the general health and behavior of the animals wereobserved which were compared to the changes caused by morphinehydrochloride in the doses of 400, 500 and 600 mg/kg.

LD₅₀ for the pain-killing composition according to the present inventionis 500 mg/kg; LD₅₀ of morphine hydrochloride is 480 mg/kg.

In order to find out the efficiency of the pain-killing preparationaccording to the present invention, clinical studies of the analgeticeffect have been performed on 115 operated and incurable oncologicalpatients. The operated patients received the pain-killing preparationaccording to the present invention once intramuscularly 20-30 minutesprior to the end of the operation and taking the patient out ofnarcosis. The dose of the pain-killer was 8 ml per 70 kg of the patientbodyweight (i.e. from 0.57 to 0.7 mg/kg as calculated for standardmorphine hydrochloride).

Various compositions of the pain-killing preparation according to thepresent invention and their efficiency are given hereinbelow in Table 2.The duration of the pain-killing effect was recordedencephalographically. Encephalograms were taken during the period of thedreamy state of the patient every two hours. The efficiency of thepain-killing was determined by the number of patients having theduration of the pain-killing effect of more than 22 hours as percentageof the total number of the patients subjected to the experiments.

                  TABLE 2                                                         ______________________________________                                                              Molecular                                                                     weight of  Concentration                                No.   Operation type  PVP        of PVP, g/l                                  ______________________________________                                        1.    Uterus extirpation                                                            with appendages (49                                                           patients)       30,000     250                                          2.    Gastroectomy, stomach                                                         resection, retroperi-                                                         toneal tumor resection                                                        (39 patients)   30,000     270                                          3.    er recti, er sigmae,                                                          colectomy (15                                                                 patients)       35,000     300                                          4.    Incurable patients                                                            (18 patients)   40,000     310                                          ______________________________________                                        Morphine                                                                      hydrochloride                                                                           Duration of pain-killing                                                                         Efficiency                                       concentration,        Number of  of pain-killing                              g/l       Time, hours patients   (22 hours), %                                ______________________________________                                        6.25      12          9          65.3                                                   18          8                                                                 24          15                                                                36          17                                                      6.00      12          6          63.6                                                   18          6                                                                 24          17                                                                36          14                                                      5.5       12          1          80.0                                                   18          2                                                                 24          8                                                                 35          4                                                       5.0       12          2          72.2                                                   18          3                                                                 24          13                                                                36          --                                                      ______________________________________                                    

It follows from the above Table 2 that the pain-killing effect afteruterus extirpation is 65.3%, after gastroectomy--63.6%, the effect ofpain-killing in patients operated for cancer of er recti, er sigmae,colectomy is 80%.

Pain-killing in incurable patients was also carried out once at the rateof 8 ml of the preparation according to the present invention per 70 kgof the patient bodyweight for a period of from 4 to 20 days. The effectof pain-killing is 72%.

In all the studied patients, in addition to assessment of thepain-killing duration, there was recorded twice daily the acid-alkalistate of blood, an electrocardiogram was taken and arterial bloodpressure and frequency of cardiac contractions were also measured.

In investigations of the acid-alkali blood state no substantialdeviations from the norm were observed. Average data for the II-nd bloodsampling (6 hours after the completion of the operation): pH=7.4±0.0045,BE=0.17±0.43 mequiv/l; pCO₂ =40.12±1.43 mm Hg at p below 0.01.

The results of ECG investigations have shown that the pain-killingpreparation according to the present invention does not affect cardiacactivity. The effect of the pain-killer according to the presentinvention on the breathing functions has been studied by means ofspirography in 12 patients 6 and 12 hours after completion of theoperation.

During the entire period of the effect of the pain-killing preparationaccording to the present invention the patients' breathing was moreprofound and uniform as compared to the initial one. Increase of thebreathing volume by 22.2%, surplus of the vital capacity of lungs by 27%and reduction of the minute volume of breathing by 0.5% (p below 0.01)are observed. Thus, the data supports the conclusion that morphine inthe pain-killing preparation according to the present invention fullyloses its depressing effect on breathing due to its constant lowconcentration in the patient's blood plasma--from 0.25 to 0.16 μg/ml.

For the therapeutist it is especially important that a patient stillremains contactable after the administration of the pain-killingpreparation during the entire period of its effect.

For incurable patients the pain-killing preparation according to thepresent invention should be administered 2 times a day in order toensure a high activity of a patient (up to walking and self-service athome). In doing so the pain syndrome is fully absent.

In the case of use of the pain-killing preparation according to thepresent invention the efficiency of pain-killing (over 22 hours) is 70%.A low viscosity of the polymer with the selected, according to theinvention, molecular mass does not cause the formation of tissueinfiltrates and it is fully withdrawn from the organism. Furthermore, inthe use of this preparation the risk of adaptation thereto is absent,despite the presence of morphine hydrochloride.

BEST MODE FOR CARRYING-OUT THE INVENTION

The pain-killing preparation according to the present invention isproduced by dissolving a mixture of poly-N-vinylpyrrolidone and morphinehydrochloride in water at a temperature within the range of from 40° to50° C. The resulting yellowish solution after filtration is poured intoampules which are sealed and sterilized for 45 minutes.

Poly-N-vinylpyrrolidone is produced by a conventional method comprisingradical polymerization of N-vinylpyrrolidone in mass or solution in thepresence of molecular-mass regulators such as R-OOH, e.g. hydrogenperoxide (1-10% by weight) of the starting N-vinylpyrrolidone. Thepolymerization is carried out in an autoclave at a temperature withinthe range of from 20° to 100° C. In the case of radical polymerizationin a solvent, as the latter use is made of water or aqueo-organicsolvents.

INDUSTRIAL APPLICABILITY

The pain-killing preparation according to the present invention finds anextensive use in medicine for surgical operations, as well as forincurable oncological patients as an analgetic possessing a long-termeffect.

We claim:
 1. A pain-killing composition comprisingpoly-N-vinylpyrrolidone having a molecular mass of 30,000 to 40,000,morphine hydrochloride and water, said poly-N-vinylpyrrolidone beingpresent in an amount between 250 and 310 grams per liter of water andsaid morphine hydrochloride being present in an amount between 5 and6.25 grams per liter of water.
 2. A method of reducing pain comprisingadministering, to a warm-blooded animal, a pain-killing effective amountof the composition of claim
 1. 3. The method of claim 2 wherein saidamount is between 0.57 and 0.7 mg/kg of bodyweight.